First, there is a reversible association of a drug molecule and a drug receptor molecule; subsequently, there is a dissociation of one drug-drug receptor complex molecular entity and a related response.

In occupation theory what is assumed about binding sites?

It is assumed that there is one binding site per receptor molecule; however; receptor molecules with multiple binding sites may also be modeled after this.

Occupation theory of drug action does not accomodate what?

This theory does not accomodate allosteric binding (in which as more and more receptors get bound, the pharmacodynamic response increases in magnitude until a maximum response is attained).

What is an agonist?

A drug/ligand that produces the maximal pharmacologic effect.

What is a partial agonist?

A drug/lignad that produces an effect that is less than maximal.

What is an antagonist?

A drug/ligand that elicits no effect but rather inhibits the receptors interaction with a second agent. (so a receptor blocker or a competitive inhibitor)(so antagonizes an agonist of a receptor from eliciting an effect)

What is an example of an antagonist?

Beta-blockers.

What is a spare receptor?

In occupation theory, it is where the maximal pharmacologic effect is achieved with only a portion of available receptors, the other receptors are spare receptors.

What is a drug's potency?

The concentration required to achieve a specified pharmacologic effect. The more potent a drug, the less of it is required for an effect (relative to its less potent counterpart)

When comparing 2 drugs which takes less time to reach the same effect?

The more potent one.

What does it mean when two drugs are said to be equipotent?

They have the same effect. For example, a 400mg drug and a 200mg drug can be equipotent but the 200mg dose is the more potent of the two.

What does rate theory state?

That the pharmacologic response depends on the rate of association of the drug and the drug receptor (rather than on the drug-drug receptor complex concentration)

What does the rate theory predict?

1. That an agonist or antagonist rapidly associate with a receptor to form a complex.

2. an agonist dissociates rapidly to produce a response

3. an antagonist would dissociate slowly to maintain an antagonistic response (just sits there, in the way)

What does a plot of pharmacologic response verses dose yield?

A hyperbolic curve; if a log-linear scale is used, a sigmoid curve is obtained.

For many drugs, ranging from between 20% and 80% of the maximal response, there is a linear relation on the log dose-response curve. Since the apparent volume of distribution is constant, the response is also proportional to the log concentration.

What is the equation for the drug effect at concentration C?

E = mlogC + e

E = effect

m = slope

e = intercept on y-axis

Using a linear portion of a log dose-pharmacologic response plot, there is a linear decline with time for a drug that follows ? ? ?.

One-compt kinetics.

A pharmacologic effects rate of decline depends on the values of what?

k and m.

Thus for a drug that has a long half-life, k is small, the rate of decline is small, and so the pharmacologic effect lasts longer.

(so high t1/2 = low k = increased effect)

What does Rmax represent?

the maximum pharmacologic response

Is the response-dose curve linear?

No

What is an integrated pharmacologic response a measure of?

The total pharmacologic response. It is the product of the duration and intensity of drug action.

Where are both the intensity and duration of drug action obtainable from?

From the Cp verses time curve described by the pharmacokinetic model.

If a bolus iv dose is divided into a smaller number of doses where is the greatest increase in the integrated response observed?

If it is divided into two equal doses (rather than 3 or 4 or 5 etc...). So a bolus dose may produce a pharmacologic effect different from that produced by administering divided doses of a drug.

Why is it not possible, with some drugs, to correlate pharmacologic response to kinetics? Give an example.

Because of complex intermediate steps involved in the former. For instance there is no direct correlation of warfarin's anticoagulant effect and its plasma concentration (a correlation is possible between Cp and the prothrombin complex production rate).

Extremely rapid drug absorption can have ? effects.

They can have detrimental effects. (for ex. this is why ER niacin is preferred, because it is notorious for causing flushing, a burning sensation).

The abuse potential of drugs increases when?

When they are available for administration by routes that allow for very rapid absorption. (ex. the contrast between the chewing of coca leaves and the use of the cocaine alkaloid)

A drug with a low k has a ? Teff (duration of pharmacological activity, or how long the drug will be effective once administered)

low k = high teff

In the eqn for pharmacologic activity (teff), why does doubling the dose NOT lead to a doubling of the duration of activity?

Because it's logarithmic.

A ten-fold dose increase only increases teff by ?%.

50%

What will double the duration of activity for a drug?

Doubling the elimination half-life or halving k.

What does the max effect model describe?

It describes the drug action in terms of the EC50 (the drug conc. that produce 50% of the max effect) and the max effect (Emax)

E = ((Emax)(C))/((E)(C50) + C)

What plot is the max effect model consistent with?

Hyperbolic plot

What is EC50 a good guide for?

For achieving drug concentrations within the therapeutic range.

EC50 is ? for any given drug.

Specific (gives and idea of how potent it is)

The max effect model represents a ? process. What does this mean.

A saturable process. So there is no improvement of pharmacologic effect after receptors get saturated or other limiting factors set in. In other words, beyond the concentration that produces the max effect, increases in concentration are ineffectual.

What is the Sigmoid Emax model?

An extension of the max effect model (emax model). It is able to describe allosteric effects.

What is the eqn for the Sigmoid Emax model? What happens if n = 1? What happens if n > 1? What would a large n value indicate?

E = ((Emax)(C^n))/((E)(C50) + (C^n))

n = number of drug molecules that bind to each receptor molecule

If n = 1 then this eqn reduces to the max effect model eqn.

If n > 1, the value of n influences the slope of the curve.

A large n values indicates allosteric effects.

The effect compartment is a ? compartment?

An effect compartment is a pharmacodynamic compartment.

What is a paradox that occurs when observing the effect compt?

The highest response is seen at the time when you have the lowest concentration of the drug in the plasma.

Only ? fraction of a drug is available for pharacologic action.

Only unbound fraction.

In the effect compartment k is typically which order?

first-order

What is the effect compartment?

A hypothetical pharmacodynamic compt; not a part of the pharmacokinetic model.

What does the effect compt explain?

The fact that the time course of the pharmacologic response may not be parallel to that of the plasma drug concentration.

When observing the effect compt what can be observed about drug movement?

Drug (free unbound drug) only moves from plasma compt to the effect compt. There is no significant transfer in the opposite direction.

In the effect compt transfer rates are typically of what order?

Typically first-order.

The effect compt. takes up a ? proportion of the drug dose (so that plasma levels are ? ?).

Takes up a negligible proportion of the drug dose so that plasma level are not affected.

What is the pharmacologic effect determined by?

From the rate constant Ke0 and the concentration of the drug in the effect compartment Ce.

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